Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome
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ABSTRACT:
PROVIDER: EGAS00001005229 | EGA |
REPOSITORIES: EGA
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Project description:We performed a prospective investigation in Sézary syndrome by the application of a standardized multiparameter flow cytometry, FACS-cell sorting, and RNA-sequencing for an in-depth immunophenotypic and transcriptional profiling of Sézary cells.
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Project description:This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689â98] Keywords: aCGH, COBRA, FISH, PLA In this multicenter study, we aimed to obtain a detailed catalogue of numerical and structural chromosomal abnormalities in a group of 20 well-defined Sz patients using high-resolution array-based CGH in combination with combined binary ratio labeling (COBRA), fluorescence in situ hybridization (FISH), and in situ proximity ligation assays (PLA).
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Primary outcome(s): The primary objective is to assess the feasibility of CMC-001© as a contrast medium in liver MRI scanning in patients with liver metastases in comparison with gadolinium BOPTA (MultiHance©) MRI.
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Project description:Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder owing to the defects in one of the factors implicated in nucleotide excision repair (NER) system. The effect of NER deficiency on melanocyte biology has not received much attention up to now from a mechanistic standpoint, due to the lack of an appropriate model. Therefore, we decided to generate XPC-deficient primary melanocytes by CRISPR-Cas9 technology, herein after called ©-XPC melanocytes. To this end, we designed two gRNA for exon 9 close to the most common XPC mutation (i.e. c.1643_1644delTG). These gRNA were cloned into lentiviral vectors containing the Cas9 nuclease and puromycin selection cassettes. Following transduction with lentivirus, melanocytes sustainably expressing Cas-9 and scramble gRNA (©-Ctrl) or gRNA targeting XPC gene (©-XPC) were subjected to PCR analysis, Sanger sequencing and western blotting. Following validation of our model, ©-Ctrl and ©-XPC melanocytes were subjected to a quantitative label-free differential proteomic analysis.
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Project description:Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is a malignancy of mature, skin-homing T cells. Sézary syndrome (Sz) is often considered to represent a leukemic phase of MF. In this study the pattern of numerical chromosomal alterations in MF tumor samples was defined using array-based CGH; simultaneously gene expression was analyzed using microarrays. Highly recurrent chromosomal alterations in MF include copy number gain of 7q36, 7q21-7q22 and loss of 5q13 and 9p21. This pattern characteristic of MF differs markedly from chromosomal alterations observed in Sz. Integration of data from array-based CGH and gene expression analysis yielded several candidate genes with potential relevance in the pathogenesis of MF. We confirmed that the FASTK and SKAP1 genes, residing in loci with recurrent gain, demonstrated increased expression. The RB1 and DLEU1 tumor suppressor genes showed diminished expression associated with loss. In addition, it was found that presence of chromosomal alterations on 9p21, 8q24 and 1q21-1q22 was associated with poor prognosis in patients with MF. This study provides novel insight into genetic alterations underlying MF. Furthermore, our analysis uncovered genomic differences between MF and Sz, which suggest that the molecular pathogenesis and therefore therapeutic requirements of these CTCLs may be distinct. To identify candidate oncogenes and tumor suppressor genes residing in chromosomal regions with recurrent copy number alteration in MF. To this end chromosomal alteration and gene expression patterns of 22 MF tumor samples were integrated to determine which genes located in minimal common regions (MCRs) with CNA demonstrated dysregulated expression associated with chromosomal alteration Keywords: aCGH and gene expression integration 22 tumors for aCGH and gene expression
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Project description:Cutaneous T-cell lymphomas represent a heterogeneous group of lymphoproliferative disorders characterized by the infiltration and expansion of mature malignant T-cells into the skin. The disease encompasses distinct variants such as mycosis fungoides a skin resident variant, in which the malignant cells are restricted to skin lesions, and leukemic variant sézary syndrome characterized by circulating malignant T-cells. Here we integrated shallow whole genome sequencing and whole exome sequencing, on samples from four sézary syndrome patients and two advanced mycosis fungoides patients with blood involvement, to characterize genetic alterations and assess their therapeutic actionability. We identified an elevated copy number of 17q, resulting in increased STAT5 expression and activation, as a key factor in the pathophysiology of the disease.
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